Microbiologically active quaternary ammonium compounds



v ing 3,361,794 MlCROBlOLOGICALLY ACTIVE QUATERNARY AMMONIUM COMPOUNDSReginald L. Wakeman, Philadelphia, Pa, and Joseph F.

Coates, Washington, D.C., assignors, by niesne assignments, toMillmaster Onyx Corporation, New York, N.Y., a corporation of New YorkNo Drawing. Filed Apr. 3, 1964, Ser. No. 357,263 8 Claims. (Cl.260--501.15)

The present invention has for its object the prepara tion of relativelywater-insoluble, microbiologically active compounds by reaction ofcertain quaternary ant-- monium hydroxides or their Water-soluble saltswith alkylsubstituted aromatic carboxylic acids or their water-solublesalts.

The quaternary ammonium compounds used in the process of this inventionare all bacteriologically active, having a phenol coefiicient of atleast 100 with respect to both Staphylococcus aureus and Salmonellaiyp'hosa at 20 C., when determined by the standard method given in theUnited States Department of Agriculture Circular No. 198. They containat least one carbon chain having from 8 to 22 carbon atoms and alsopossess at least one benzyl radical attached to the quaternary nitrogenatom. The benzyl radical may, if desired, be substituted by alkyl groupsor halogen atoms. The quaternary ammonium compounds, moreover, possessonly non-heterocyclic nitrogen atoms. In general, the quaternaryammonium compounds used in the present invention comply with theformula:

where R is an alkyl radical containing from 8 to 22 carbon atoms, analkyl benzyl radical in which the benzyl group may contain a substituentmethyl radical and in which the alkyl group contains 8 to 22 carbonatoms, or an alltyl phenoxy ethoxy ethyl radical in which the phenylgroup'may contain a substituent methyl radical and R is a benzyl orsubstituted benzyl radical, or a methyl group if R is an all-:yl benzylradical containing eight or more on )Ol'l atoms in its alkylsubstituent. X in the above formula is chlorine, bromine, iodine,sulfate, methosulfate, ethosulfate and the like.

Typical examples of these quaternary ammonium compounds are alkyldimethyl benzyl ammonium chloride in which the alkyl group may have from8 to 22 carbon atoms, alkyl dimethyl substituted benzyl ammoniumchlorides, in which the alkyl radical contains from 8 to 22 carbon atomsand in which the benzyl radical is substituted with one or more sidechains Containing from 1 to 5 carbon atoms such, for example, as methyl,dimethyl, trimethyl, tetramethyl, ethyl, diethyl, isopropyl, tertiarybutyl and isoamyl or with one, two, or more, halogen atoms such aschlorine or bromine, alkyl dimethyl menaphthyl ammonium chloride andalkyl dimethyl tctrahydromenaphthyl ammonium chloride in which the alkylradical contains from 8 to 22 carbon atoms, alkyl benzyl trimethylammonium chloride in which the alkyl radical contains from 8 to 22carbon atoms and in which the aromatic nucleus of the benzyl radicalmay, if desired, be substituted by one or more methyl or other loweralkyl groups, alkyl phenoxy ethoxy ethyl dimethyl benzyl ommoniumchloride in which the alkyl radical may be isooctyl or nonyl, andmixtures of the aforesaid quaternary ammonium compounds.

The alkyl-aromatic monocarboxylic acids which are :d Jan. 2, i968 usedin the present invention correspond. to the general formula RZCO H wheren is any number from zero to four.

Typical examples of the alkyl-aryl. carboxylic acids which may be usedin the practice of this in ention. in clude o, mand ptoluic acids, thevarious isomer:z at dimethyl benzoic acid and trimethyl benzoic acid, oill" and p ethyl or isopropyl benzoic acid, hexyl, octyl, or decylbenzoic acid and the like, methylor ethylcinnamic acid or hydrocinnamicacid, the various isomers of meth, l== naphthoic acid the like.

The compounds of this invention may be prepared by mixing an aqueoussolution of the quaternary ammonium salt or hydroxide ot the kinddefined above with an aqm ous solution of the acid in question or withany of water-soluble salts.

After thorough mixing, the organic product layer arated from the aqueouslayer (as with a separatory fun nel) since two distinct phases areformed. Separation may be facilitated by the addition of an organicsolvent; im-- miscible with water. The product layer may be washed withwater to remove any residual by-product salt r unreacted materials. Thesolvent, if any, may be evaporated and the product air or vacuum driedto a paste, wax; oil or solid.

It is not necessary to use an aqueous medium. A vent or solvent mixturein which the starting materia soluble will be satisfactory. Non-acqueoussolvents facilitate the separation of by-product inorganic salt andrcduce the need for vacuum drying to get an anhydrous product. When anon-aqueous medium is employed, it usually necessary to add a smallamount or; water to tacilitate ionic reaction.

The product may be used, if desired, without drying since any entrappedwater is irrelevant to the microbiological activity of the compounds. Inother applications, removal of Water may be essential for reasons notrelated to biological activity.

An alternative method for the preparation of cont pounds especiallyapplicable to the treatment: of fabric, ropes, net, woven and non-wovenfabric and reticulated or convoluted materials, involves a twostepprocess. in the first step, the material is passed through a bath containing the anionic moiety. Excess solution is removed by methods wellknown to those skilled in the art. The treated material is then passedthrough a, second bath wherein the concentration of quaternary ammoniumcompound is such that the material pickup will result in an. equivalentamount of quaternary ammonium compound reacting with the anionic moiety,depositing the product in the most intimate way on the surface and inthe interstices, convolutions and reticulations of the material.

The method of adjustment of solution concentration to achieve therequired pickup is well known to those skilled in the art. The order oftreatment may be reversed with out atfecting the biological activity ordurability of the product on the material. The products of thisinvention may be formulated as Water dispersions by dissolving them in awater-miscible organic solvent such as acetone or methanol and dilutingwith water or by dissolving them in emulsifiable oils such, for example,as sulfonated castor oil or pine oil and diluting with water. Inpreparing aqueous dispersions, emulsifying agents such, for example.

as ethylene oxide condensates of alkyl phenols may be used with orwithout organic solvents.

It is surprising that the compounds of this invention exsolubility inwater. Because of their unusual combnation of physical andmicrobiological properties, they can be used to impart laundry-resistantanti-microbial characteristics to textiles. They can also be used as theactive agent in antimildew finishes for textiles which are resistant toleaching with water.

Although the compounds have low water solubility, they are compatiblewith various organic solvents, plasticizers and high molecular weightcompounds. Consequently, they may be incorporated as anti-microbialagents in synthetic resins and plastics. The compounds are compatiblewith natural and synthetic rubber latices. Therefore, they may be usedto prepare bactcriostatic illms and molded objects deposited from suchlatices.

The compounds can be incorporated into cutting and grinding fluidswithout precipitation. Also, they blend well with non-ionic and anionicsurface active agents. In such compositions they retain theirmicrobiological activity.

It will be understood that the properties of the products describedherein will vary depending upon the nature of the quaternary ammoniumcompound used in their prep-- aration as well as the aromatic carboxylicacid or salt reacted therewith.

The chemical, physical and biological properties of the products of ourinvention make them especially approlpriate for the followingapplications when. suitably incororated in active amounts in anappropriate vehicle, bind- };rer, medium or substrate:

(I) Mildewproofing fabric, canvas, ropes, textiles, awn" ings, sails,tcnting and other woven and non-woven reticulated materials.

I (2) Paint inildewstats.

i (3) let plane fuel additive to control growth of micro- I organisms.

(4) Odor preservative agents for clothes and shoes.

(5) Mildew retardant and odor suppressant for shoes and other leatherproducts.

(6) Topical antiseptics.

(7) Antidandrufl agents.

(8) Disinfection agents for hair and gut of man and beast.

(9) Bacteriostatic furniture dressing.

(10) Surface finishes for stone, plaster, tile, cement. brick and otherinorganic building materials. to retard growth of microorganisms, fungi,mold and algaev l l) Wool preservative.

(12) Plant and tree spray to combat fungi.

(l3) Antimycotic agents for soap wrappers.

(i-l) Self-sanitizing brushes.

( l5) Mildewproofing agent in and on plastic and film.

(16) h lildewproofing of cellulosics, cardboard. fibre board. paper andcorclage.

(17) Contact biostat for application to film, waxes and cloth topreserve cheese. meats and Vegetables and other food products.

(18) Algal inhibition, especially on surfaces and in solution where lowfoaming is desirable.

(19) Paper pulp slime control.

(20) Sanitizing agent for rug, carpet, curtains.

(21) Egg preservation.

(22) Adhesive preservation.

(23) Preservation of latex paints.

(24) Preservation of metalworking compounds.

(25) Additives for soap and for both anionic and non-= ionic detergentsin liquid, bar, powder, bead, solution and other forms to impartbacteriostatic and fungistatic properties thereto.

The microbiological activity of our compounds has been evaluated formicrobiological stasis by the Standard Tube Dilution Test, the techniquefor which is common knowledge to those skilled in the art. A Difco Bacto4 CSMA Broth #0826 was used in the study. This test is used to determinethe lowest concentration of microbiologically active compounds whichwill inhibit the growth of. the organism in question. For a wide rangeof applications, the inhibition of growth rather than outright kill issatisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of theCSMA Broth in a test tube which is then sterilized in an autoclave. Onecc. solution of the microbiologically active compound at an appropriateconcentration is added to the test tube which is then inoculated with0.l cc. of a twenty-four hour old culture of the organism under study.The test tube is then incubated at 37 C. for forty-eight hours andobserved 'Qor bacterial growth.

The same procedure is followed for fungi. i such tests. however, thetubes are incubated for fourteen days at a temperature suitable foroptimum fungal growth, usual ly 25 C.

The invention is illustrated by, but not restricted to, the followingexamples:

Example I A stock solution was prepared containing 5% by weight of thesodium salt of p-toluic acid. To a vigorously agitated aliquot of thissolution containing 0.04l equivalent weight of the compound was addedthe chemical y equiv alent amount of an 11% solution of a commercialgrade of alkyl dimethyl ethyl-benzyl ammonium chloride (Onyx ChemicalCorporation, BTC471, in which the alkyl diStributiOn is C12, C14, C16,C18) The agitated mixture was poured into a separatory funnel andseparated into two phases. The organic product layer was removed andvacuum dried to a yellow paste, in. theoretical yield, of alkyl dimethylethyl-benzyl ammonium p-toluate.

Similar products were prepared by replacing the ptoluic acid withm-toluic acid and otoluic acid.

Example 11 The solution of sodium p-toluate of Example l was treated inthe same manner and in the same amount with a chemically equivalentamount of a solution of a com mercial grade of; alkyl dimethyl benzylammonium chloride (Onyx Chemical Corporation, ETC-824," in which thealkyl distribution is 60% C 30% C 5% C 5% C The agitated mixture wastransferred to a separatory funnel and separated into two phases. Theseparated or ganic compound layer on vacuum drying yielded a whitepaste, in theoretical yield, of alkyl dimethyl benzyl ammonium,p-toluate.

Similarly, by substituting m-toluic acid for p-toluic acid, the alkyldimethyl benzyl ammonium m-toluate was obtained in theoretical yield.

Example I]! A stock solution was prepared containing 5% by weight of thesodium salt of octyl-benzoic acid. An aliquot con taining 0.064equivalent weight of the compound was agitated vigorously, while addingthe chemically equiv alcnt amount of an ll% solution of the alkyldimcthyl benzyl ammonium chloride of Example ll. The agitated mixturewas separated in a separatory funnel. The organic product. layer wasvacuum dried to a yellow paste. in theoretical yield, of alkyl dimethylbenzyl ammonium octyl-benzoate.

Example I V The products of: Example I and ll were tested by theStandard Tube Dilution Test described above against Staphylococcus(Ill/(HIS (8.4.), Sa/nm/zellu Iyp/mm (St) and Aspergillus nigcl (A.15.). Results are shown in Table l.

We claim: 1. A compound having the structure:

wherein R is a member of the group consisting of alkyl, alkyl benzyl,alkyl methyl-benzyl, alkyl phenoxy ethoxy ethyl and alkyl phenoxy ethoxyethyl having a methyl substituent on the phenyl group, the alkyl in eachcase having 8 to 22 carbon atoms, R" is a member of the group consistingof benzyl, lower alkyl-substituted benzyl and methyl, R" being methylwhen R is alkyl benzyl, R is a member of the group consisting of alkylsubstituted benzene, alkyl substituted naphthalene, alkyl substituteddiphenyl and alkyl substituted diphenyl oxide, said alkyl having 1 to 22carbon atoms, and Z is a member of the group consisting of (CH and (CH),,-2H wherein n is a number from to 4.

2. The compound as defined in claim 1, wherein the carboxylic acid isselected from the group consisting of o-, m, and p-toluic acids,dimethyl benzoic acid, trimethyl benzoic acid and its isomers, 0-, mandp-ethyl benzoic acids, o-, mand p-isoproyl benzoic acid, o-, mandp-hexyl benzoic acid, o-, mand p-octyl benzoic acid, o-, mand p-decylbenzoic acid, o-, m and p-methyland ethyl-cinnamic and hydrocinnamicacids, and methyl naphthoic acids, and its isomers.

3. Alkyl dimethyl ethyl-benzyl ammonium p-toluate wherein the alkyl has12 to 18 carbon atoms.

4. Alkyl dimethyl ethyl-benzyl ammonium p-toluate wherein the alkyl has12 to 18 carbon atoms.

5. Alkyl dimethyl ethyl-benzyl ammonium o-toluate wherein the alkyl has12 to 18 carbon atoms.

6. Alkyl dimethyl benzyl ammonium p-toluate wherein the alkyl has 12 to18 carbon atoms.

7. Alkyl dimethyl benzyl ammonium m-toluate where in the alkyl has 12 to18 carbon atoms.

8. Alkyl dimethyl benzyl ammonium octyl-benzoate wherein the alkyl has12 to 18 carbon atoms,

References Cited UNITED STATES PATENTS 2,108,765 2/1938 Domagk 260-5672,676,986 4/1954 Wakeman et a1. 260567 2,695,840 11/1954 Leppla 260-501OTHER REFERENCES Ishidate et 211.: J. Pharm. Soc., Japan 69, 518-52(1949), CA. relied on, vol. 44, column 4202b (1950),

LORRAINE A. WEINBERGER, Primary Examiner.

M. WEBSTER, Assistant Examiner.

1. A COMPOUND HAVING THE STRUCTURE: